RU2013130609A - HUMANIZED ANTIBODIES TO LIV-1 AND THEIR APPLICATION FOR TREATMENT OF CANCER - Google Patents

HUMANIZED ANTIBODIES TO LIV-1 AND THEIR APPLICATION FOR TREATMENT OF CANCER Download PDF

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RU2013130609A
RU2013130609A RU2013130609/10A RU2013130609A RU2013130609A RU 2013130609 A RU2013130609 A RU 2013130609A RU 2013130609/10 A RU2013130609/10 A RU 2013130609/10A RU 2013130609 A RU2013130609 A RU 2013130609A RU 2013130609 A RU2013130609 A RU 2013130609A
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seq
humanized antibody
variable region
heavy chain
mature variable
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RU2608646C2 (en
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Мария Лея СМИТ
Джанго САСМАН
Уильям АРТУР
Альбина НЕСТЕРОВА
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Сиэтл Генетикс, Инк.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A61K47/6865—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from skin, nerves or brain cancer cell
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • C07K16/3015—Breast
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • C07K16/3053—Skin, nerves, brain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • C07K16/3069—Reproductive system, e.g. ovaria, uterus, testes, prostate
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/46—Hybrid immunoglobulins
    • C07K16/461—Igs containing Ig-regions, -domains or -residues form different species
    • C07K16/464—Igs containing CDR-residues from one specie grafted between FR-residues from another
    • C07K16/465—Igs containing CDR-residues from one specie grafted between FR-residues from another with additional modified FR-residues
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
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    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/52—Constant or Fc region; Isotype
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    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565—Complementarity determining region [CDR]
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    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
    • C07K2317/732—Antibody-dependent cellular cytotoxicity [ADCC]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Abstract

1. Гуманизированное антитело, содержащее зрелый вариабельный участок тяжелой цепи, имеющий аминокислотную последовательность, по меньшей мере на 90% идентичную SEQ ID NO: 53, при условии, что положение Н27 занято L, положение Н29 занято I, Н30 - Е и Н94 - V, и зрелый вариабельный участок легкой цепи, по меньшей мере на 90% идентичный SEQ ID NO: 60, при условии, что положение L36 занято Y и положение L46 - Р.2. Гуманизированное антитело по п. 1, содержащее три гипервариабельных участка CDR из SEQ ID NO: 53 и три CDR из SEQ ID NO: 60.3. Гуманизированное антитело по п. 1 или 2 при дополнительном условии, что положение Н76 занято N.4. Гуманизированное антитело по п. 1, содержащее зрелый вариабельный участок тяжелой цепи, имеющий аминокислотную последовательность, по меньшей мере на 95% идентичную SEQ ID NO: 53, и зрелый вариабельный участок легкой цепи, по меньшей мере на 95% идентичный SEQ ID NO: 60.5. Гуманизированное антитело по п. 1, где зрелый вариабельный участок тяжелой цепи слит с константным участком тяжелой цепи, и зрелый вариабельный участок легкой цепи слит с константным участком легкой цепи.6. Гуманизированное антитело по п. 1, где константный участок тяжелой цепи представляет собой мутантную форму природного константного участка человека, который имеет пониженное связывание с рецептором Fc-гамма по сравнению с природным константным участком человека.7. Гуманизированное антитело по п. 1, где константный участок тяжелой цепи относится к изотипу IgG1.8. Гуманизированное антитело по любому из пп. 1 или 7, где константный участок тяжелой цепи имеет аминокислотную последовательность, содержащую SEQ ID NO: 44, и константный участок легкой цепи имеет аминокислотную последовательность, со1. Humanitariannet antibody containing a mature variable region of the heavy chain having an amino acid sequence of at least 90% identical to SEQ ID NO: 53, provided that the position H27 is occupied L, position H29 is I, H30 - E and H94 - V and a mature light chain variable region at least 90% identical to SEQ ID NO: 60, provided that position L36 is Y and position L46 is P.2. The humanized antibody of claim 1, comprising three hypervariable CDR regions from SEQ ID NO: 53 and three CDRs from SEQ ID NO: 60.3. The humanized antibody according to claim 1 or 2, with the additional condition that the H76 position is occupied N.4. The humanized antibody of claim 1, comprising a mature variable region of the heavy chain having an amino acid sequence of at least 95% identical to SEQ ID NO: 53, and a mature variable region of the light chain of at least 95% identical to SEQ ID NO: 60.5 . The humanized antibody of claim 1, wherein the mature variable region of the heavy chain is fused to a constant region of the heavy chain, and the mature variable region of the light chain is fused to a constant region of the light chain. The humanized antibody of claim 1, wherein the heavy chain constant region is a mutant form of a natural human constant region that has reduced binding to the Fc-gamma receptor compared to the natural human constant region. The humanized antibody of claim 1, wherein the constant region of the heavy chain is of the IgG1.8 isotype. The humanized antibody according to any one of paragraphs. 1 or 7, where the constant region of the heavy chain has an amino acid sequence containing SEQ ID NO: 44, and the constant region of the light chain has an amino acid sequence, with

Claims (42)

1. Гуманизированное антитело, содержащее зрелый вариабельный участок тяжелой цепи, имеющий аминокислотную последовательность, по меньшей мере на 90% идентичную SEQ ID NO: 53, при условии, что положение Н27 занято L, положение Н29 занято I, Н30 - Е и Н94 - V, и зрелый вариабельный участок легкой цепи, по меньшей мере на 90% идентичный SEQ ID NO: 60, при условии, что положение L36 занято Y и положение L46 - Р.1. Humanitariannet antibody containing a mature variable region of the heavy chain having an amino acid sequence of at least 90% identical to SEQ ID NO: 53, provided that the position H27 is occupied L, position H29 is I, H30 - E and H94 - V and a mature light chain variable region at least 90% identical to SEQ ID NO: 60, provided that position L36 is Y and position L46 is P. 2. Гуманизированное антитело по п. 1, содержащее три гипервариабельных участка CDR из SEQ ID NO: 53 и три CDR из SEQ ID NO: 60.2. The humanized antibody of claim 1, comprising three hypervariable CDR regions from SEQ ID NO: 53 and three CDRs from SEQ ID NO: 60. 3. Гуманизированное антитело по п. 1 или 2 при дополнительном условии, что положение Н76 занято N.3. The humanized antibody according to claim 1 or 2, with the additional condition that the H76 position is occupied by N. 4. Гуманизированное антитело по п. 1, содержащее зрелый вариабельный участок тяжелой цепи, имеющий аминокислотную последовательность, по меньшей мере на 95% идентичную SEQ ID NO: 53, и зрелый вариабельный участок легкой цепи, по меньшей мере на 95% идентичный SEQ ID NO: 60.4. The humanized antibody according to claim 1, containing a mature variable region of the heavy chain having an amino acid sequence of at least 95% identical to SEQ ID NO: 53, and a mature variable region of the light chain of at least 95% identical to SEQ ID NO : 60. 5. Гуманизированное антитело по п. 1, где зрелый вариабельный участок тяжелой цепи слит с константным участком тяжелой цепи, и зрелый вариабельный участок легкой цепи слит с константным участком легкой цепи.5. The humanized antibody of claim 1, wherein the mature variable region of the heavy chain is fused to a constant region of the heavy chain, and the mature variable region of the light chain is fused to the constant region of the light chain. 6. Гуманизированное антитело по п. 1, где константный участок тяжелой цепи представляет собой мутантную форму природного константного участка человека, который имеет пониженное связывание с рецептором Fc-гамма по сравнению с природным константным участком человека.6. The humanized antibody of claim 1, wherein the heavy chain constant region is a mutant form of a natural human constant region that has reduced binding to the Fc-gamma receptor compared to the natural human constant region. 7. Гуманизированное антитело по п. 1, где константный участок тяжелой цепи относится к изотипу IgG1.7. The humanized antibody of claim 1, wherein the constant region of the heavy chain is of the IgG1 isotype. 8. Гуманизированное антитело по любому из пп. 1 или 7, где константный участок тяжелой цепи имеет аминокислотную последовательность, содержащую SEQ ID NO: 44, и константный участок легкой цепи имеет аминокислотную последовательность, содержащую SEQ ID NO: 42.8. The humanized antibody according to any one of paragraphs. 1 or 7, where the constant region of the heavy chain has an amino acid sequence containing SEQ ID NO: 44, and the constant region of the light chain has an amino acid sequence containing SEQ ID NO: 42. 9. Гуманизированное антитело по п. 1, где константный участок тяжелой цепи имеет аминокислотную последовательность, содержащую SEQ ID NO: 46 (S239C), и константный участок легкой цепи имеет аминокислотную последовательность, содержащую SEQ ID NO: 42.9. The humanized antibody of claim 1, wherein the heavy chain constant region has an amino acid sequence comprising SEQ ID NO: 46 (S239C) and the light chain constant region has an amino acid sequence containing SEQ ID NO: 42. 10. Гуманизированное антитело по п. 1 при условии, что любые отличия в CDR зрелого вариабельного участка тяжелой цепи и зрелого вариабельного участка легкой цепи от SEQ ID NO 52 и 60, соответственно, находятся в положениях Н60-Н65.10. The humanized antibody according to claim 1, provided that any differences in the CDRs of the mature variable region of the heavy chain and the mature variable region of the light chain from SEQ ID NOS 52 and 60, respectively, are at positions H60-H65. 11. Гуманизированное антитело по п. 1, где зрелый вариабельный участок тяжелой цепи имеет аминокислотную последовательность, обозначенную как SEQ ID NO: 52 или 53, и зрелый вариабельный участок легкой цепи имеет аминокислотную последовательность, обозначенную как SEQ ID NO: 59 или 60.11. The humanized antibody of claim 1, wherein the mature variable region of the heavy chain has the amino acid sequence designated as SEQ ID NO: 52 or 53, and the mature variable region of the light chain has the amino acid sequence designated as SEQ ID NO: 59 or 60. 12. Гуманизированное антитело по п. 1, где зрелый вариабельный участок тяжелой цепи имеет аминокислотную последовательность, обозначенную как SEQ ID NO: 53, и зрелый вариабельный участок легкой цепи имеет аминокислотную последовательность, обозначенную как SEQ ID NO: 60.12. The humanized antibody of claim 1, wherein the mature variable region of the heavy chain has the amino acid sequence designated as SEQ ID NO: 53 and the mature variable region of the light chain has the amino acid sequence designated as SEQ ID NO: 60. 13. Гуманизированное антитело по п. 1, где антитело конъюгировано с цитотоксическим или цитостатическим агентом.13. The humanized antibody according to claim 1, wherein the antibody is conjugated to a cytotoxic or cytostatic agent. 14. Гуманизированное антитело по п. 1, имеющее константу ассоциации в отношении LIV-1 человека или яванского макака от 0,5 до 2×109 М-1.14. The humanized antibody according to claim 1, having an association constant for human LIV-1 or cynomolgus monkey from 0.5 to 2 × 10 9 M -1 . 15. Гуманизированное антитело, содержащее зрелый вариабельный участок тяжелой цепи, содержащий три CDR согласно Kabat из SEQ ID NO: 52, где положение Н27 занято L, положение Н29 занято I, Н30 - Е, Н76 - N и Н94 - V, и зрелый вариабельный участок легкой цепи, содержащий три CDR согласно Kabat из SEQ ID NO: 60, при условии, что положение L36 занято Y, и положение L46 - Р.15. Humanitariannet antibody containing a mature variable region of the heavy chain containing three CDRs according to Kabat from SEQ ID NO: 52, where position H27 is occupied L, position H29 is I, H30 - E, H76 - N and H94 - V, and mature variable a light chain region containing three CDRs according to Kabat of SEQ ID NO: 60, provided that position L36 is Y and position L46 is P. 16. Нуклеиновая кислота, кодирующая зрелый вариабельный участок тяжелой цепи и/или зрелый вариабельный участок легкой цепи, как определено по любому из пп. 1-15.16. A nucleic acid encoding a mature variable region of a heavy chain and / or a mature variable region of a light chain, as defined by any one of claims. 1-15. 17. Способ лечения пациента, имеющего рак или подверженного риску рака, включающий введение пациенту эффективного режима гуманизированного антитела по любому из пп. 1-15.17. A method for treating a patient having cancer or at risk of cancer, comprising administering to the patient an effective humanized antibody regimen according to any one of claims. 1-15. 18. Способ по п. 17, где рак является раком молочной железы, раком предстательной железы, раком шейки матки или меланомой.18. The method of claim 17, wherein the cancer is breast cancer, prostate cancer, cervical cancer, or melanoma. 19. Фармацевтическая композиция, содержащая гуманизированное антитело по любому из пп. 1-5.19. A pharmaceutical composition comprising a humanized antibody according to any one of claims. 1-5. 20. Гуманизированное антитело, содержащее зрелый вариабельный участок тяжелой цепи, имеющий аминокислотную последовательность, по меньшей мере на 90% идентичную НВ (SEQ ID NO: 10), и зрелый вариабельный участок легкой цепи, по меньшей мере на 90% идентичный LB (SEQ ID NO: 5).20. Humanitariannet antibody containing a mature variable region of the heavy chain having an amino acid sequence of at least 90% identical to HB (SEQ ID NO: 10), and a mature variable region of the light chain of at least 90% identical to LB (SEQ ID NO: 5). 21. Гуманизированное антитело по п. 20, содержащее зрелый вариабельный участок тяжелой цепи, имеющий аминокислотную последовательность, по меньшей мере на 95% идентичную НВ, и зрелый вариабельный участок, по меньшей мере на 95% идентичный LB.21. The humanized antibody of claim 20, comprising a mature heavy chain variable region having an amino acid sequence of at least 95% identical to HB and a mature variable region of at least 95% identical to LB. 22. Гуманизированное антитело по п. 20 или 21, при условии, что положения Н29, Н30 и Н76 заняты I, Е и N, и L36 занято Y.22. The humanized antibody according to claim 20 or 21, provided that the provisions of H29, H30 and H76 are occupied by I, E and N, and L36 is occupied by Y. 23. Гуманизированное антитело по п. 20, при условии, что любое различие в каркасах вариабельных участков зрелого вариабельного участка тяжелой цепи и SEQ ID NO: 10 выбрано из группы, состоящей из Н27, занятого F, H28, занятого N, H48, занятого I, H66, занятого К, Н67, занятого А, Н71, занятого А, Н76, занятого N, H93, занятого N, H94, занятого V, L37, занятого L, L39, занятого К, L45, занятого К, и L46, занятого L.23. The humanized antibody according to claim 20, provided that any difference in the frameworks of the variable regions of the mature variable region of the heavy chain and SEQ ID NO: 10 is selected from the group consisting of H27 occupied by F, H28 occupied by N, H48 occupied by I , H66, busy K, H67, busy A, H71, busy A, H76, busy N, H93, busy N, H94, busy V, L37, busy L, L39, busy K, L45, busy K, and L46, busy L. 24. Гуманизированное антитело по п. 20, где три CDR зрелого вариабельного участка тяжелой цепи представляют собой CDR из SEQ ID NO. 10, и три CDR зрелого вариабельного участка легкой цепи представляют собой CDR из SEQ ID NO: 15.24. The humanized antibody of claim 20, wherein the three CDRs of the mature heavy chain variable region are CDRs from SEQ ID NO. 10, and three CDRs of the mature variable region of the light chain are CDRs of SEQ ID NO: 15. 25. Гуманизированное антитело по п. 20, где зрелый вариабельный участок тяжелой цепи слит с константным участком тяжелой цепи, и зрелый константный участок легкой цепи слит с константным участком легкой цепи.25. The humanized antibody of claim 20, wherein the mature variable region of the heavy chain is fused to a constant region of the heavy chain and the mature constant region of the light chain is fused to the constant region of the light chain. 26. Гуманизированное антитело по п. 20, где константный участок тяжелой цепи представляет собой мутантную форму природного константного участка человека, который имеет пониженное связывание с рецептором Fc-гамма по сравнению с природным константным участком человека.26. The humanized antibody of claim 20, wherein the heavy chain constant region is a mutant form of a natural human constant region that has reduced binding to the Fc-gamma receptor compared to the natural human constant region. 27. Гуманизированное антитело по п. 26, где константный участок тяжелой цепи относится к изотипу IgG1.27. The humanized antibody of claim 26, wherein the constant region of the heavy chain is of the IgG1 isotype. 28. Гуманизированное антитело по п. 25 или 27, где константный участок тяжелой цепи имеет аминокислотную последовательность, содержащую SEQ ID NO: 6, и константный участок легкой цепи имеет аминокислотную последовательность, содержащую SEQ ID NO: 4.28. The humanized antibody of claim 25 or 27, wherein the heavy chain constant region has an amino acid sequence containing SEQ ID NO: 6 and the light chain constant region has an amino acid sequence containing SEQ ID NO: 4. 29. Гуманизированное антитело по п. 26, где константный участок тяжелой цепи имеет аминокислотную последовательность, содержащую SEQ ID NO: 8 (S239C), и константный участок легкой цепи имеет аминокислотную последовательность, содержащую SEQ ID NO: 4.29. The humanized antibody of claim 26, wherein the heavy chain constant region has an amino acid sequence containing SEQ ID NO: 8 (S239C) and the light chain constant region has an amino acid sequence containing SEQ ID NO: 4. 30. Гуманизированное антитело по п. 20, при условии, что любые отличия в CDR зрелого вариабельного участка тяжелой цепи и зрелого вариабельного участка легкой от SEQ ID NO 10 и 15, соответственно, находятся в положениях Н60-Н65.30. The humanized antibody according to claim 20, provided that any differences in CDR of the mature variable region of the heavy chain and the mature variable region of light from SEQ ID NO 10 and 15, respectively, are in positions H60-H65. 31. Гуманизированное антитело по п. 20, где зрелый вариабельный участок тяжелой цепи имеет аминокислотную последовательность, содержащую SEQ ID NO: 10, и зрелый вариабельный участок легкой цепи имеет аминокислотную последовательность, содержащую SEQ ID NO: 15.31. The humanized antibody of claim 20, wherein the mature variable region of the heavy chain has an amino acid sequence comprising SEQ ID NO: 10 and the mature variable region of a light chain has an amino acid sequence containing SEQ ID NO: 15. 32. Гуманизированное антитело по п. 20, где антитело конъюгировано с цитотоксическим или цитостатическим агентом.32. The humanized antibody of claim 20, wherein the antibody is conjugated to a cytotoxic or cytostatic agent. 33. Гуманизированное антитело, содержащее зрелый вариабельный участок тяжелой цепи, содержащий 3 CDR из SEQ ID NO: 10, и где положения Н29, Н30 и Н76 заняты I, E и N соответственно, и зрелый вариабельный участок легкой цепи, содержащий три CDR из SEQ ID NO: 15, и где положение L36 занято Y.33. Humanitariannet antibody containing a mature variable region of the heavy chain containing 3 CDRs from SEQ ID NO: 10, and where the positions H29, H30 and H76 are occupied by I, E and N, respectively, and a mature variable region of the light chain containing three CDRs from SEQ ID NO: 15, and where position L36 is occupied Y. 34. Гуманизированное антитело по п. 20, имеющее большую аффинность к LIV-1, чем антитело BR2-14a.34. The humanized antibody according to claim 20, having a greater affinity for LIV-1 than the antibody BR2-14a. 35. Гуманизированное антитело по п. 20, имеющее константу ассоциации в отношении LIV-1 человека или яванского макака от 0,5 до 2×109 М-1.35. The humanized antibody of claim 20, having an association constant for human LIV-1 or cynomolgus monkey from 0.5 to 2 × 10 9 M -1 . 36. Нуклеиновая кислота, кодирующая зрелый вариабельный участок тяжелой цепи и/или зрелый вариабельный участок легкой цепи, как определено по любому из пп. 20-35.36. A nucleic acid encoding a mature variable region of a heavy chain and / or a mature variable region of a light chain, as defined by any one of claims. 20-35. 37. Способ лечения пациента, имеющего рак или подверженного риску рака, включающий введение пациенту эффективного режима гуманизированного антитела по любому из пп. 20-35.37. A method of treating a patient having cancer or at risk of cancer, comprising administering to the patient an effective humanized antibody regimen according to any one of claims. 20-35. 38. Способ по п. 37, где рак представляет собой рак молочной железы, рак предстательной железы, рак шейки матки или меланому.38. The method of claim 37, wherein the cancer is breast cancer, prostate cancer, cervical cancer, or melanoma. 39. Фармацевтическая композиция, содержащая гуманизированное антитело по любому из пп. 1-15, 20-35.39. A pharmaceutical composition comprising the humanized antibody according to any one of claims. 1-15, 20-35. 40. Способ лечения пациента, имеющего или подверженного риску тройного негативного рака молочной железы, включающий введение пациенту эффективного режима антитела, которое специфично связывается с LIV-1.40. A method of treating a patient having or at risk of triple negative breast cancer, comprising administering to the patient an effective antibody regimen that specifically binds to LIV-1. 41. Способ по п. 40, где антитело конъюгировано с цитотоксическим или цитостатическим агентом.41. The method of claim 40, wherein the antibody is conjugated to a cytotoxic or cytostatic agent. 42. Выделенный полипептид, имеющий аминокислотную последовательность, содержащую SEQ ID NO: 85, при условии, что остатки 1-28 могут быть опущены, или нуклеиновая кислота, кодирующая то же самое. 42. The selected polypeptide having an amino acid sequence containing SEQ ID NO: 85, provided that residues 1-28 can be omitted, or a nucleic acid encoding the same.
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